Nepafenac (compound I) is the international common accepted name for 2-amino-3-benzoylbenzeneacetamide, and has an empirical formula of C15H14N2O2, and a molecular weight of 254.28 g/mol.

Nepafenac is a non-steroidal anti-inflammatory active pharmaceutical substance with analgesic activity. In the United States, nepafenac is marketed under the name NEVANAC™, and is indicated for ophthalmic use.
A preparation of nepafenac and similar compounds is disclosed in U.S. Pat. No. 4,313,949 (“the '949 patent”), which is incorporated herein by reference. The '949 patent's method of preparing nepafenac is depicted herein as Scheme 1.

Preparation 7 of the '949 patent describes the production of compound (IV) by using 2-aminobenzophenone (compound of formula II), and methylthioacetamide (compound of formula III), as starting materials, tert-butyl hypochlorite as a chlorinating agent, triethylamine as a base, and a mixture of dichloromethane and tetrahydrofuran as a solvent. The '949 patent makes use of 2-amino-3-benzoyl-α-(methylthio)-benzeneacetamide (compound of formula IV), as an intermediate compound, which is converted into nepafenac (compound I) via desulfurization using Raney nickel as a catalyst as in Example 2.
However, the synthesis of compound (IV) described in the '949 patent suffers from a number of drawbacks. For example, following the teachings of Preparation 7 of the '949 patent (i.e. see Comparative Example 1), the inventors have discovered that several chlorination by-products of compound (II) and compound (IV) (e.g., 2-amino-3-benzoyl-5-chloro-α-(methylthio)benzeneacetamide, 2-amino-3-chlorobenzophenone, and 2-amino-5-chlorobenzophenone) are obtained in considerable amounts. Consequently, the inventors have observed that the preparation described in the '949 patent affords compound (IV) in low yields and with significant amounts of chlorinated by-products, which additionally cause reproducibility problems. Further, the synthesis of compound (IV) disclosed in the '949 patent requires very low temperatures, e.g., about −65° C., which is difficult to achieve at industrial scale and would involve the use of special apparatus. In addition, the chlorinating agent (i.e., tert-butyl hypochlorite) poses a handling hazard as it is unstable, light-sensitive, and decomposes explosively. Accordingly, tert-butyl hypochlorite must be stored at temperatures below 10° C.
In view of the foregoing, there is an unmet need for a reproducible, high-yielding process for preparing compound (IV) which does not produce chlorinated by-products and can be carried out at higher temperatures, wherein said process is suitable for preparing nepafenac in a large scale. There is, therefore, an unmet need for an improved process for preparing the benzoylbenzeneacetamide derivative nepafenac.